Juvenile hormone (JH), an isoprenoid which controls metamorphosis and reproduction in insects, is synthesized by specialized endocrine glands, the corpora allata (CA). The CA are controlled by neuroendocrine factors (allatotropins and allatostatins) which have not yet been characterized. The biochemical pathway for JH synthesis is well-known and does not differ from the early steps of cholesterol biosynthesis up to farnesyl pyrophosphate. However, nothing is known on the biochemical regulation of JH biosynthesis. The specific objective of this project is to test the theory that HMG-CoA reductase is the rate-limiting enzyme in JH biosynthesis. HMG-CoA reductase will be studied in the CA of adult female Diploptera punctata, because the CA of this cockroach species synthesize only one hormone (JH III) with the highest synthetic rates known for any insect. Whereas HMG-CoA reductase is controlled in mammals by a sterol- and a non-sterol feedback mechanism, it is thought that insects which do not synthesize sterols might show only the non-sterol regulation of HMG-CoA reductase. The aims of this proposal are (1) to characterize HMG-CoA reductase in D. punctata CA and compare its activity under various physiological conditions to rates of JH III synthesis, and to the activity of earlier steps (HMG-CoA synthesis) and later steps (mevalonate kinase, mevalonate and farnesol stimulation of JH III synthesis). (2) To study the possible feedback regulation of HMG-CoA reductase in response to experimentally elevated or lowered rates of isoprenoid synthesis. (3) To study the possible role of reversible phosphorylation in HMG-CoA reductase regulation. (4) More generally, to understand the biochemical mechanisms by which JH III synthesis is controlled. This study should contribute to our understanding of HMG-CoA reductase regulation in a model system where sterols are not involved and should be useful in future studies on the mode of action of allatotropins and allatostatins.